Safety and Efficacy Study of Everolimus to Treat BK Virus Infection in Kidney Transplant Recipients

This is a pilot study designed as a single center, randomized, open-label trial study
comparing the safety and efficacy of MPA discontinuation with the addition of Zortress
(everolimus) versus standard immunosuppression reduction in adult patients who have
undergone a renal transplant and who have evidence of BKV infection. All kidney transplant
recipients at UCSF are screened for BKV in the urine and plasma at months 1, 3, 6, 9, and 12
post-transplantation. The presence of viruria > 1 million copies/mL and/or viremia prompts a
50% reduction in the MPA dose as well as monthly monitoring of BKV in the urine and plasma.
Renal transplant patients found to have BK viruria > 1 million copies/mL and/or viremia >
500 copies/mL on any screening lab will be eligible for enrollment.

Before any study-related evaluations are performed, the patient must give written informed
consent. Once consent is obtained, patients will be randomized in consecutive blocks of 10,
such that there will be 5 patients allocated to each group for each block. Only the study
coordinator will have access to the block sequences. Patients will be randomized to one of
two groups: group 1 will undergo MPA discontinuation with the addition of Zortress
(everolimus) to their current regimen of tacrolimus and prednisone; group 2 will undergo a
50% dose reduction in MPA and continue with tacrolimus and prednisone.

The two groups will be as follows: All patients in group 1 will undergo discontinuation of
MPA and will receive Zortress (everolimus) at a starting dose of 0.75 mg PO b.i.d. (1.5
mg/day). Everolimus whole blood trough levels will be monitored at pre-specified time points
to achieve a range of 3-8 ng/mL. Group 1 patients will continue on prednisone and tacrolimus
with a target whole blood trough level of 3-6 ng/mL. Group 2 patients will continue with
tacrolimus (target trough level of 6-10 ng/mL), prednisone, and undergo a 50% reduction of
the MPA dose. At months 1, 2, and 3 post-randomization urine and plasma BKV levels will be
re-checked. Renal allograft biopsies will be done for cause as clinically indicated.
Tacrolimus trough levels are lower in the Zortress (everolimus) arm in order to minimize any
potential nephrotoxicity with this drug combination as well as minimize the risk of
over-immunosuppression.

In all patients, routine transplant monitoring labs will be performed monthly as part of
standard of care including a measurement of BUN and Cr, CBC, tacrolimus trough levels, urine
protein excretion and fasting lipids.

During the 3 month treatment period patients will be seen in clinic at baseline and months
1, 2, and 3 for follow-up. The assessment to address the primary objective will be performed
at the end of the treatment period (Month 3). An interim analysis will be performed once 50%
enrollment is reached.

In a sub-group of patients (30 patients total; 15 in group 1 and 15 in group 2) using our
whole-blood assay measuring p70S6 kinase phosphorylation, the investigators will investigate
the correlation between inhibition of p70S6 kinase phosphorylation with BKV replication.
Finally, by measuring both p70S6 phosphorylation inhibition as well as expression of the
NFAT-regulated genes IL-2, interferon gamma and GM-CSF, the investigators will correlate
rejection episodes in patients maintained on lower immunosuppression alone versus those on a
Zortress (everolimus) -based regimen. As patients are assigned to their intervention group
based on the randomization scheme they will be offered enrollment in this sub-group
analysis. All patients will be sequentially enrolled in the sub-group analysis until the 30
subject goal is reached with 15 subjects per group.

Inclusion Criteria:

- Male or female renal transplant recipients 18-75 years of age (primary or
re-transplant)

- Recipients of cadaveric, living unrelated or living related donor kidney

- Baseline IS consisting of tacrolimus, MPA, and prednisone

- Patients with BK viruria ≥ 1 million copies/mL and/or viremia (> 500 copies/mL) found
on routine BKV screening.

- Patients who have given written informed consent to participate in the study

Exclusion Criteria:

- Patients who are ABO incompatible transplants

- Patients with an abnormal liver profile such as ALT, AST, alkaline phosphatase, or
total bilirubin > 3x ULN at the time of randomization

- Patients with severe total hypercholesterolemia (> 350 mg/dL) or total
hypertriglyceridemia (> 500 mg/dL). Patients on lipid lowering drugs with controlled
hyperlipidemia are acceptable.

- Patients with a platelet count < 100,000/mm3 at randomization

- Patients with an ANC < 1,500/mm3 or WBC < 4.5mm3

- Patients with a known hypersensitivity to the study drug or to drugs of similar
chemical classes.

- Patients being treated with drugs (other than tacrolimus) that are potent inducers or
inhibitors of cytochrome P4503A4

- Patients who have any surgical or medical condition, such as severe diarrhea, active
peptic ulcer disease, or uncontrolled DM, which, in the opinion of the investigators,
might significantly alter the absorption, distribution, metabolism and/or excretion
of study medication.

- Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
female after conception and until the termination of gestation, confirmed by a
positive urine human chorionic gonadotrophin laboratory test

- Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, including women whose career, lifestyle, or sexual orientation
precludes intercourse with a male partner and women whose partners have been
sterilized by vasectomy or other means, UNLESS they are using two birth control
methods. The two methods can be a double barrier method or a barrier method plus a
hormonal method.

- Adequate barrier methods of contraception include: diaphragm, condom (by the
partner), intrauterine device (copper or hormonal), sponge or spermicide. Hormonal
contraceptives include any marketed contraceptive agent that includes an estrogen
and/or a progestational agent.

- Reliable contraception should be maintained throughout the study and for 7 days after
study drug discontinuation.

- Women are considered post-menopausal and not of child bearing potential if they have
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical
profile (e.g. age appropriate, history of vasomotor symptoms) or six months of
spontaneous amenorrhea with serum FSH levels > 40 mIU/mL and estradiol < 20 pg/mL] or
have had surgical bilateral oophorectomy (with or without hysterectomy) at least six
weeks ago. In the case of oophorectomy alone, only when the reproductive status of
the woman has been confirmed by follow up hormone level assessment is she considered
not of child bearing potential.

- Patients with baseline urine protein excretion > 500mg/day

- Patients with eGFR < 40 ml/min

- Patients who have undergone desensitization